We hypothesize that early detection, targeting aggressive prostate cancer, will enable survival benefits of treatment for lethal disease, and reduce harms of over-treatment for indolent disease. Toward this goal, we assemble biospecimen sample sets via rigorous SOP's in cohorts designed to avoid bias. We provide these specimens and guidance regarding study design to Discovery Labs, industry and consortia. Team efforts between the DMCC, the Hopkins BRL, industry partners, UTHSC-SA and our CVC facilitated FDA approval of the Prostate Health Index (phi - with data from our CVC's first cycle), and urinary PCA3 (with data from the current cycle). In two funding cycles, our CVC enrolled 4,821 subjects. We helped advance the TMPRSS2:Erg fusion (T2:Erg) discovery by the Chinnaiyan BDL toward actionable clinical use, completing 3 Aims with progress on the 4th: First, we combined urinary detection of T2:Erg with urinary PCA3 to improve specificity of detecting cancers with Gleason score > 7, validated this algorithm in a multi-center cohort, and showed the potential to reduce health care cost via this algorithm in men less than 65 years old. Second, we characterized community-based distribution of urinary T2:Erg, PCA3, and phi independent of PSA screening, and found race- based differences in these parameters, paving the way for a phase IV screening trial (separate proposal under review by DOD). Third, we compared prostatectomy tissue Erg expression to urinary T2:Erg, guiding the range of appropriate urinary T2:Erg cut-points to reflect tissue status. Fourth, we procured biopsies from two nation- wide, retrospective watchful waiting cohorts (PHS and HPFS), enrolled subjects onto the PASS Trial, and assembled a biospecimen set suitable for evaluating multiplex RNA's to discern aggressive from indolent disease. Recognizing limitations of T2:Erg as a classifier of cancer aggressiveness, we initiated clinical translation of a 24-gene, multiplex RNA panel for discerning aggressive from indolent prostate cancer; showed the feasibility of this assay in biopsy tissue and urine, and identified an industry partner to evaluat this signature on a clinical grade platform. We will expand our validation studies to include imaging to assess cancer severity based on FACBC, a PET radiotracer undergoing clinical development. We are expanding the breadth of our CVC from previously being limited to academic medical centers (AMC's), to now including an urban indigent care hospital, a Veterans Administration Medical Center, and a suburban community hospital (in addition to our host AMC) so that we project enrolling 1050 African-American men, substantially diversifying the EDRN biospecimen resource. We now propose the following Aims: 1) To validate the combination of urine PCA3, T2:Erg and serum phi as predictive of aggressive prostate cancer de novo and for active surveillance; 2) To validate a multiplex RNA signature of aggressive prostate cancer in biopsy samples and post-DRE urine; 3) To validate FACBC as imaging to detect occult metastatic disease in high-risk, localized prostate cancer; 4) To collaborate with EDRN BDL's, CVC's and BRL's to advance prostate cancer biomarker development.